Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined human papillomavirus (HPV) typing and the status of ATM, chk2, CDC25C, cdc2 and cyclinB1 in cervical intraepithelial neoplasia (CIN) and invasive cancer (IC). A total of 93 samples [normal: 10; CIN: 34 (CINI:9, CINII:12, CINIII:13); IC: 49 (stage I:10, stage II:21, stage III:15, stage IV:3)] were included in this study. HPV status was evaluated by the PCR non-radioactive HPV detection system. We analyzed ATM, chk2, CDC25C, cdc2 and cyclinB1 protein expression by immunohistochemistry. HPV DNA was detected in 73.5% of 34 CINs and 89.8% of 49 ICs. Detection of HPV subtypes 16 and 18 was more frequent in ICs (46.9%) than in CINs (23.5%) (p=0.0387). Abnormal expression of ATM, chk2, CDC25C, cdc2 and cyclinB1 were 2.9%, 32.4%, 2.9% 20.6% and 0% in CINs and 8.2%, 30.6%, 10.2%, 46.9% and 12.2% in ICs. The alteration of cdc2 was higher in ICs than in CINs (p=0.0198). Altered expression of cdc2 was higher in HPV16 and 18 cases (69.6%) than in other cases (26.9%) (p=0.0042). However, the relationship between HPV typing and ATM, chk2, CDC25C and cyclinB1 expression was not significant. Cdc2 is implicated in cervical carcinogenesis and may be related to p53 inactivation by HPV.
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PMID:Relationship between HPV typing and the status of G2 cell cycle regulators in cervical neoplasia. 1528 42

Angiotensin II has mitogenic and angiogenic effects and its receptors are widespread, particularly in epithelial tissue. Tissue renin angiotensin systems (tRASs) may be a local source of angiotensin II that has specific paracrine functions. To investigate the presence of a tRAS in normal human breast and tumours. Immunocytochemistry, and quantitative RT-PCR was used to establish: (i) the presence and localisation of RAS components, (ii) the possibility of their involvement in cancer. (1) mRNA coding for angiotensinogen, prorenin, angiotensin converting enzyme (ACE), and both AT1 and AT2 receptors was demonstrated in normal and diseased breast tissues. (2) (pro)renin was identified in epithelial cells in both normal and diseased tissue, but in invasive carcinoma, its distribution was mostly confined to fibroblasts or could not be detected at all. (3) Angiotensin converting enzyme was shown in epithelial cells in both normal and malignant tissue. The results are consistent with the hypothesis that a tRAS is present in the breast, and is disrupted in invasive cancer.
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PMID:Localisation of renin-angiotensin system (RAS) components in breast. 1675 91

DNA repair pathways can enable tumor cells to survive DNA damage induced by chemotherapy and thus provide prognostic and/or predictive value. We evaluated Affymetrix gene expression profiles for 145 DNA repair genes in untreated breast cancer (BC) patients (n = 684) and BC patients treated with regimens containing neoadjuvant taxane/anthracycline (n = 294) or anthracycline (n = 210). We independently assessed estrogen receptor (ER)-positive/HER2-negative, HER2-positive, and ER-negative/HER2-negative subgroups for differential expression, bimodal distribution, and the prognostic and predictive value of DNA repair gene expression. Twenty-two genes were consistently overexpressed in ER-negative tumors, and five genes were overexpressed in ER-positive tumors, but no differences in expression were associated with HER2 status. In ER-positive/HER2-negative tumors, the expression of nine genes (BUB1, FANCI, MNAT1, PARP2, PCNA, POLQ, RPA3, TOP2A, and UBE2V2) was associated with poor prognosis, and the expression of one gene (ATM) was associated with good prognosis. Furthermore, the prognostic value of specific genes did not correlate with proliferation. A few genes were associated with chemotherapy response in BC subtypes and treatment-specific manner. In ER-negative/HER2-negative tumors, the MSH2, MSH6, and FAN1 (previously MTMR15) genes were associated with pathological complete response and residual invasive cancer in taxane/anthracycline-treated patients. Conversely, PMS2 expression was associated with residual invasive cancer in treatments using anthracycline as a single agent. In HER2-positive tumors, TOP2A was associated with patient response to anthracyclines but not to taxane/anthracycline regimens. In genes expressed in a bimodal fashion, RECQL4 was significantly associated with clinical outcome. In vitro studies showed that defects in RECQL4 impair homologous recombination, sensitizing BC cells to DNA-damaging agents.
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PMID:DNA repair gene patterns as prognostic and predictive factors in molecular breast cancer subtypes. 2407 19

Nasopharyngeal carcinoma (NPC) is a highly invasive cancer with poor prognosis. One of the recurring themes of NPC biology and treatments is DNA damage. Epstein-Barr virus infection, which is generally accepted as a key etiological factor for NPC, triggers DNA damage responses. In normal cells, DNA damage checkpoints are able to prevent cell cycle progression following DNA damage and are critical for maintaining genome stability. Main features of the checkpoints include activation of ATM and ATR by sensors of DNA damage, which activates effector kinases CHK1 and CHK2; they in turn targets the CDC25/WEE1-cyclin B1-CDK1 axis to cause G(2) arrest, or the p53-p21(CIP1/WAF1) and pRb pathways to cause G(1) arrest. Significantly, these checkpoints are typically disrupted in NPC cells. While mutations are relatively rare, mechanisms including promoter modifications, miRNAs, and actions of Epstein-Barr virus-encoded proteins such as EBNA3C and LMP1 have been described. Paradoxically, radiation-mediated DNA damage remains the primary treatment of NPC. How dysregulation of the DNA damage checkpoints contribute to NPC tumorigenesis and responses to treatment remain poorly understood. In this review, the current understanding of the molecular mechanisms of the various DNA damage checkpoints and what is known about them in NPC are discussed.
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PMID:DNA damage checkpoints in nasopharyngeal carcinoma. 2450 38

Nasopharyngeal carcinoma (NPC) is a rare but highly invasive cancer. As radiotherapy is the primary treatment for NPC, this offers a rationale to investigate if uncoupling the DNA damage responses can sensitize this cancer type. The G2 DNA damage checkpoint is controlled by a cascade of protein kinases: ATM/ATR, which phosphorylates CHK1/CHK2, which in turn phosphorylates WEE1. A number of small molecule inhibitors have been developed against these kinases as potential therapeutic agents. Here we demonstrated that compare to that in immortalized nasopharyngeal epithelial cells, ATR, CHK1, and WEE1 were overexpressed in NPC cell lines. Inhibitors of these kinases were unable to promote extensive mitotic catastrophe in ionizing radiation-treated NPC cells, indicating that they are not very effective radiosensitizer for this cancer. In the absence of prior irradiation, however, mitotic catastrophe could be induced with inhibitors against CHK1 (AZD7762) or WEE1 (MK-1775). NPC cells were more sensitive to WEE1 inactivation than nasopharyngeal epithelial cells. Targeting CHK1 and WEE1 together induced more extensive mitotic catastrophe than the individual components alone. Taken together, our results show that NPC cells depend on CHK1 and WEE1 activity for growth and that inhibitors of these kinases may serve as potential therapeutics for NPC.
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PMID:Pharmacological inactivation of CHK1 and WEE1 induces mitotic catastrophe in nasopharyngeal carcinoma cells. 2602 28

Ductal carcinoma in situ (DCIS) is a noninvasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer whereas others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome, and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty-two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor-intrinsic subtypes, proliferative, immune scores, and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like, or ERBB2(+)) displayed signatures characteristic of activated Treg cells (CD4(+)/CD25(+)/FOXP3(+)) and CTLA4(+)/CD86(+) complexes indicative of a tumor-associated immunosuppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly, ncRNA and methylation profiles reproduce changes observed postinvasion. Among the most significant findings, we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a preinvasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer.
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PMID:A Molecular Portrait of High-Grade Ductal Carcinoma In Situ. 2624 78